Primary Biliary Cholangitis (PBC) is an idiopathic, chronic autoimmune cholestatic disease characterized by female predominance, circulating antimitochondrial antibodies, non- suppurative small bile duct cholangitis, and progressive cholestasis which can result in end- stage liver disease if not recognized and treated. Despite strong evidence of immunologic involvement, the precise autoimmune initiating pathways remain unclear. Furthermore, while bile acid modulators have been able to impact disease management, immunomodulating therapies have proven unsuccessful to date. Macrophage Migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine that mediates the host response to infection and stress by activating key innate and adaptive immune pathways. MIF's bioactivity and MIF polymorphisms have been implicated in multiple autoimmune disorders. The applicant initiated the first investigation of MIF in autoimmune liver diseases and current research under a K08 has focused on the role of MIF and its receptor CD74 in autoimmune hepatitis (AIH). Novel preliminary data suggests that MIF may also be critical for antigen-specific cholangitis caused by T-cells. Furthermore, preliminary data from the recently described ARE-Del (-/-) model of autoimmune cholangitis, which closely mimics many features of PBC and is induced by chronic overexpression of IFN?, demonstrated significant overexpression of both CD74 and MIF. These data suggest a potential key role of MIF-CD74 in mediating autoimmune cholestasis. Therefore, the hypotheses of this project are that the immune-based pathogenesis of PBC critically depends on T-cell and hepatic MIF and CD74 expression, and that modulation of the MIF-CD74 cellular pathway prevents development and attenuates the progression of injury. To experimentally test this, Aim 1 will define the role of T-cell MIF expression in the OVA BIL mouse model of cholangitis, and test the ability of a novel small molecule MIF antagonist (MIF098) to prevent biliary injury. Aim 2 will define the role of MIF and CD74 in the ARE-Del (-/-) mouse by generating a novel ARE-Del (-/-)/CD74 KO mouse and by also using a pharmacotherapeutic approach with MIF098. The proposed experiments are expected to demonstrate that MIF and CD74 are critically important in autoimmune cholangitis and that pharmacotherapy with anti-MIF immunomodulation is effective in pre-clinical PBC models.